1. Field of the Art
The present invention refers to a new process for the preparation of venlafaxin, which is an antidepressant and is the international non-proprietary name (INN) for (xc2x1)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol, and/or the physiologically acceptable addition salts thereof.
2. Prior Art Reference
Venlafaxin, of formula 
as well as processes for the preparation thereof, are described in the document U.S. Pat. No. 4,535,186 and it is usually marketed as the hydrochloride of the racemic form thereof.
In the Spanish documents ES-A-527938 and ES-A-544402 and in document U.S. Pat. No. 4,535,186 giving priority thereto, several processes for the preparation of venlafaxin are described. Other processes are also described in J. P. Yardley et al. J. MED. Chem. 1990. 33:2899-2905 and in the document U.S. Pat. No. 5,043,466.
The processes for the preparation of venlafaxin described in the afore-mentioned documents may be represented as shown in Scheme 1 of reaction sequences. 
In the document ES-A-527938 and in the document U.S. Pat. No. 4,535,186, as well as in the article of J. P Yardley et al., the process is described which consists of preparation the amide 2, starting out from the carboxylic acid 1, to introduce in said amide the cyclohexanol residue by means of the formation of an enolate anion, by reacting with n-butyl-lithium, and later condensation of said enolate anion with cyclohexanone, giving place to the amide 3 which is reduced to give venlafaxin.
On the other hand, in the document ES-A-544402, as well as in the document U.S. Pat. No. 4,535,186 and in the article of J. P. Yardley et al., a alternative process is described consisting of introducing the cyclohexanol residue in the nitrilo 4, in the same way as in the previous case, to obtain the intermediate 5 that is reduced to the amine 6 by catalytic hydrogenation with a catalyst such as, for example, 5% rhodium on alumina. In this case, the final stage consists of the double methylation of the amine 6 to obtain venlafaxin, although appreciable amounts of a by-product, of formula 
are formed during said reaction that should be reduced under more energetic conditions to lead to the preparation of venlafaxin.
In the document U.S. Pat. No. 4,535,186 a very similar path is also described which starts out from a starting product 7, in which the group G can bexe2x80x94COOH, xe2x80x94COOxe2x88x92, xe2x88x92COOR (R being alkyl), xe2x80x94CHO and xe2x80x94CH2OH, so as, using the same strategy already commented upon, to introduce the cyclohexanol residue and later, in a variable number of stages that depends on the nature of the group G selected, to convert the intermediate 8 into venlafaxin.
On the other hand, in the document U.S. Pat. No. 5,043,466, a variant of the last two ways mentioned is described consisting of conducting the reaction of introduction of the cyclohexanol residue using a selection of certain hydrocarbon solvents and using groups G such as nitrilo, N,N-dimethylamido and N,N-dimethylthioamido.
As may be appreciated, all the above well-known processes share the same strategy of synthesis, consisting of introducing the cyclohexanol residue by condensation of cyclohexanone with an enolate anion of an arylacetic acid, or of a synthetic analogue thereof, and subsequently to modify the carboxylic group derivative or analogue thereof, to convert it into the N,N-dimethylaminomethyl group.
All the abovementioned cases are complicated time-consuming processes which, furthermore, are not very appropriate industrially, since necessarily require the use of a strong base, such as n-butyl-lithium, to form the enolate anion and, therefore, the use of rigorously anhydrous reaction conditions, inert atmosphere, and very low reaction temperatures.
There still remains, therefore, the need to have new alternative processes for the preparation of venlafaxin that are simpler and of easier industrial adaptation.
The object of the present invention is a process for the preparation of venlafaxin of easy industrial adaptation based on the use of easily obtainable starting products and intermediates.
The process of the present invention for the preparation of venlafaxin and/or the physiologically acceptable addition salts thereof, consists essentially of reacting a compound of general formula (II) 
where R is a C1-C10 alkyl, aryl, aralkyl or cycloalkyl group of 3 to 6 atoms of carbon, with a organomagnesium compound of general formula (III) 
where X is an atom of halogen, preferably bromine and, if desired, a salt of the thus prepared venlafaxin is formed by reaction thereof with a physiologically acceptable acid.
The compound of formula (II) may be prepared by conventional methods, well-known to the man of the art, among which may be mentioned those which are reflected in the reaction sequences of Scheme 2 starting out from p-methoxyphenylacetic esters. 
As shown in Scheme 2, the ester (IV) may be reacted with dimethylformamide dialkylacetal to give place to a xcex2-(N,N)-dimethylamino)-xcex1-(p-methoxyphenyl)acrylic ester (VI), which can be reduced, either by metallic hydrides such as NaBH4 or LiAIH4 or by catalytic hydrogenation, to give the compound (II).
The intermediate (VI) can also be thus obtained by formylation of the ester (IV) to give place to the intermediate (V), followed by the reaction of said intermediate (V) with dimethylamine.
If desired, although it is not necessary to follow this alternative, which is not the preferred one, it is also possible to prepare compound (II) directly from the ester (IV) by formation of the enolate anion thereof, for example with lithium diisopropylamide (LDA), followed by reaction of said enolate anion with an appropriate Eschenmosher salt, for example N,N-dimethylmethyleneimmonium iodide.
As far as the organomagnesium compounds of formula (III) are concerned, can be acquired on the marketplace, such as for example in the preferred case of pentamethylene-1,5-bis(magnesium bromide), or can be easily prepared from the corresponding 1,5-dihalopentane by reaction with magnesium in an inert solvent, such as tetrahydrofuran.
Compound (II) and the organomagnesium compound (III) may be reacted in an inert solvent, an inert solvent being understood to be any that in the opinion of the man of the art does not substantially react with the reactants involved. Preferred among the inert solvents are the non-cyclic and cyclic ethers, with diethyl ether, tetrahydrofuran, dioxane, etc. being particularly preferred.
The most appropriate reaction temperatures are those ranging from 0xc2x0 C. to the reflux temperature of the selected solvent.
Once the venlafaxin base has been prepared, if desired it can be converted, by way of conventional techniques known to the man of the art, into an addition salt with an physiologically acceptable inorganic or organic acid, among which there may be cited without limitative character: hydrochloric, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, citric, maleic, malic, fumaric, etc. acids. It is preferred to use hydrochloric acid as the physiologically acceptable acid to form the venlafaxin addition salt.
The following examples are given for the purpose of providing the man of the art with a sufficiently clear and complete explanation of the present invention, but should not be considered as limitations to the essential aspects of the object thereof, as have been disclosed in the foregoing paragraphs hereof.